Intracellular Invasion of Orientia tsutsugamushi Activates Inflammasome in ASC-Dependent Manner

Orientia tsutsugamushi, a causative agent of scrub typhus, is an obligate intracellular bacterium, which escapes from the endo/phagosome and replicates in the host cytoplasm. O. tsutsugamushi infection induces production of pro-inflammatory mediators including interleukin-1β (IL-1β), which is secreted mainly from macrophages upon cytosolic stimuli by activating cysteine protease caspase-1 within a complex called the inflammasome, and is a key player in initiating and maintaining the inflammatory response. However, the mechanism for IL-1β maturation upon O. tsutsugamushi infection has not been identified. In this study, we show that IL-1 receptor signaling is required for efficient host protection from O. tsutsugamushi infection. Live Orientia, but not heat- or UV-inactivated Orientia, activates the inflammasome through active bacterial uptake and endo/phagosomal maturation. Furthermore, Orientia-stimulated secretion of IL-1β and activation of caspase-1 are ASC- and caspase-1- dependent since IL-1β production was impaired in Asc- and caspase-1-deficient macrophages but not in Nlrp3-, Nlrc4- and Aim2-deficient macrophages. Therefore, live O. tsutsugamushi triggers ASC inflammasome activation leading to IL-1β production, which is a critical innate immune response for effective host defense

Silent Synapses, LTP, and the Indirect Parallel-Fibre Pathway: Computational Consequences of Optimal Cerebellar Noise-Processing

Computational analysis of neural systems is at its most useful when it uncovers principles that provide a unified account of phenomena across multiple scales and levels of description. Here we analyse a widely used model of the cerebellar contribution to sensori-motor learning to demonstrate both that its response to intrinsic and sensor noise is optimal, and that the unexpected synaptic and behavioural consequences of this optimality can explain a wide range of experimental data. The response of the Marr-Albus adaptive-filter model of the cerebellar microcircuit to noise was examined in the context of vestibulo-ocular reflex calibration. We found that, when appropriately connected, an adaptive-filter model using the covariance learning rule to adjust the weights of synapses between parallel fibres and Purkinje cells learns weight values that are optimal given the relative amount of signal and noise carried by each parallel fibre. This optimality principle is consistent with data on the cerebellar role in smooth pursuit eye movements, and predicts that many synaptic weights must be very small, providing an explanation for the experimentally observed preponderance of silent synapses. Such a preponderance has in its turn two further consequences. First, an additional inhibitory pathway from parallel fibre to Purkinje cell is required if Purkinje cell activity is to be altered in either direction from a starting point of silent synapses. Second, cerebellar learning tasks must often proceed via LTP, rather than LTD as is widely assumed. Taken together, these considerations have profound behavioural consequences, including the optimal combination of sensori-motor information, and asymmetry and hysteresis of sensori-motor learning rates

Chronic Achilles tendon rupture reconstruction using a modified flexor hallucis longus transfer

The purpose of this study was to report the management and outcome of 11 patients presenting with chronic Achilles tendon (AT) rupture treated by a modified flexor hallucis longus (FHL) transfer. Seven patients presented with a neglected AT rupture, one with a chronic AT rupture associated with Achilles tendinosis and three with an AT re-rupture. AT defect after fibrosis debridement averaged 7.4 cm. In addition to FHL transfer, we performed an augmentation using the two remaining fibrous scar stumps of the ruptured AT. Functional assessment was performed using the AOFAS score and isokinetic evaluation was performed to assess ankle plantarflexion torque deficit. Follow-up averaged 79 months. Functional outcome was excellent with a significant improvement of the AOFAS score at latest follow-up. No re-rupture nor major complication, particularly of wound healing, was observed. All patients presented with a loss of active range of motion of the hallux interphalangeal joint without functional weakness during athletic or daily life activities. Isokinetic testing at 30 degrees/second and 120 degrees/second revealed a significant average decrease of 28 ± 11% and 36 ± 4.1%, respectively, in plantarflexion peak torque. Although strength deficit persisted at latest follow-up, functional improvement was significant without morbidity due to FHL harvesting. For patients with chronic AT rupture with a rupture gap of at least 5 cm, surgical repair using FHL transfer with fibrous AT stump reinforcement achieved excellent outcomes